Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

Abstract

a b s t r a c tThe principle functions of neuroinflammation are to limit tissue damage and promote tissue repair in response to pathogens or injury. While neuroinflammation has utility, pathophysiological inflammatory responses, to some extent, underlie almost all neuropathology. Understanding the mechanisms that control the three stages of inflammation (initiation, propagation and resolution) is therefore of critical importance for developing treatments for diseases of the central nervous system. The purinergic signaling system, involving adenosine, ATP and other purines, plus a host of P1 and P2 receptor subtypes, controls inflammatory responses in complex ways. Activation of the inflammasome, leading to release of pro-inflammatory cytokines, activation and migration of microglia and altered astroglial function are key regulators of the neuroinflammatory response. Here, we review the role of P1 and P2 receptors in mediating these processes and examine their contribution to disorders of the nervous system. Firstly, we give an overview of the concept of neuroinflammation. We then discuss the contribution of P2X, P2Y and P1 receptors to the underlying processes, including a discussion of cross-talk between these different pathways. Finally, we give an overview of the current understanding of purinergic contributions to neuroinflammation in the context of specific disorders of the central nervous system, with special emphasis on neuropsychiatric disorders, characterized by chronic low grade inflammation or maternal inflammation. An understanding of the important purinergic contribution to neuroinflammation underlying neuropathology is likely to be a necessary step towards the development of effective interventions.

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

“…New therapy approaches of TLE have been focused on brain inflammation, highlighting the interest of purinergic P2X7 receptors (P2X7R) as potent mediator of neuroinflammation in the epileptic brain [7][8][9][10][11][12][13][14][15][16][17][18]. P2X7R are trimeric non-selective ligandgated ion channels activated by ATP, permeable to mono-and divalent cations (permeability: Ca 2+ > Na + > K + ), resulting in the rapid depolarization of the membrane [19,20].…”

The Role of Nucleotides in Glial Cells during Peripheral Nerve Trauma and Compressive Disorders

“…Uridine nucleotides activate specific P2Y receptor subtypes in humans [102,103], acting as cell-to-cell signaling in the nervous system [104,105]. They are dependent on the activity of the axonal signals in neighboring oligodendrocytes and their structure consists of seven transmembrane domains, with the N-terminal domain in the extracellular space and the C-terminal domain in the cytoplasm [19,106].…”

“…Subtypes of UTP-activated receptors P2Y2 and P2Y4 in humans are coupled to G q protein [102] and are mainly involved in long-term effects, such as differentiation, neurite outgrowth, and cell survival or death [108,109]. These receptors are normally activated during pathological conditions and participate in inflammatory processes of the nervous system [102], in which they trigger and sustain reactive astrogliosis, the reaction to brain trauma [104,105], characterized by cellular proliferation and neural circuit remodeling [110].…”

“…These receptors are normally activated during pathological conditions and participate in inflammatory processes of the nervous system [102], in which they trigger and sustain reactive astrogliosis, the reaction to brain trauma [104,105], characterized by cellular proliferation and neural circuit remodeling [110].…”

“…P2Y2 receptors are expressed by neurons, astrocytes, and microglia and regulate actin polymerization and cytoskeletal rearrangements through the Rac/Rho pathways [112], as well as the P2Y4 receptors [113]. Its activation confers neuroprotection in several ways: the promotion of neurite outgrowth, increased cell motility, nonamyloidogenic processing of the amyloid precursor protein, and increased phagocytosis and degradation of the amyloid-beta peptide [102,111]. Moreover, studies have shown that microglia respond rapidly to nerve lesions by migrating to the spinal projection territories of the central terminals of injured primary afferents, with subsequent proliferation, activation of p38 MAPK and ERK1/2, and production of proinflammatory cytokines and chemokines [114].…”